Advanced Bladder Cancer: Check Mate or Check Point Inhibitors

Transcription

1 Advanced Bladder Cancer: Check Mate or Check Point Inhibitors Daniel P Petrylak, MD Professor of Medicine and Urology Director, GU Translational Working Group Co Director, Signal Transduction Program Smilow Cancer Center, Yale University

2 Disclosure Consultant: Sanofi Aventis, Celgene, Pfizer, Millineum, Dendreon, Johnson and Johnson, Bayer, Medivation, Roche/Genetech, Bellcium, Tyme Research Support: Roche, Merck, Dendreon, Progenics, Lilly, Medivation, Agenysis, Astra Zenca, GSK, Bayer Stock Tyme, Bellicum

3

4

5 Mechanism of Immune Checkpoint Inhibitors IFNg-mediated upregulation of tumor PD-L1 Key Attributes of the Immune System Specificity Memory Adaptive Stromal PD-L1 modulation of T cells B7.1 PD-L1/PD-1-mediated inhibition of tumor cell killing Herbst RS et al. J Clin Oncol. 2013;31(suppl; abstr 3000) Priming and activation of T cells Immune cell modulation of T cells PD-L2-mediated inhibition of TH 2 T cells Cancer cells develop many mutations that can make them appear foreign to the immune system T cells can recognize, attack and kill these foreign cancer cells Cancer cells can evade immune attack by expressing PD-L1 Adaptive tumor expression of PD-L1 turns the immune system OFF Clinically, we want to block PD-1 or PD-L1 to reactivate the immune system PD-L1 plays an important role in dampening the anti-tumor immune response

6 Checkpoint Inhibitors Approved for Use in Urothelial Carcinoma 7 US FDA Approvals May 2016-May 2017 Setting Antibody Approval Status First-line Atezolizumab Accelerated approval granted in April (cisplatinineligible) Pembrolizumab Accelerated approval granted in May Platinumpretreated Atezolizumab Accelerated approval granted in May In May 2017, the subsequent phase 3 IMvigor211 trial did not meet primary endpoint of overall survival. Nivolumab Accelerated approval granted in February Durvalumab Accelerated approval granted in May Avelumab Accelerated approval granted in May Pembrolizumab Full approval granted in May 2017.

7 Approvals: First-line, Cisplatin- Ineligible Apr 2017 May 2017 Atezolizumab Pembrolizumab Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy.

8 IMvigor210 (Cohort 1) IMvigor210: Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Cohort 1 (N = 119): 1L cisplatin-ineligible Tumor tissue evaluable for PD-L1 testing a Cohort 2 (N = 310): Platinum-treated muc Cohort 1 specific inclusion criteria No prior treatment for muc (>12 mo since perioperative chemo) ECOG PS 0-2 Cisplatin ineligibility 1 based on 1 of the following: Renal impairment: GFR <60 and >30 ml/min Grade 2 hearing loss or peripheral neuropathy ECOG PS 2 Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression Atezolizumab 1200 mg IV q3w until loss of clinical benefit Key primary endpoint : Confirmed ORR: RECIST v1.1 (per central IRF) Key secondary endpoints : DOR, PFS, OS, safety Balar et al. Lancet. 2017;389:67

9 IMvigor210 (Cohort 1) N = 119 ORR = 23% (9% CR) Overall Survival Balar et al. Lancet. 2017;389:67

10 KEYNOTE-052: Pembrolizumab as 1st-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Cancer Patients (N = 350) Advanced urothelial cancer No prior chemotherapy for metastatic disease ECOG PS 0-2 Ineligible for cisplatin based on 1 of the following: CrCl <60 ml/min ECOG PS 2 Grade 2 neuropathy or hearing loss NYHA class III CHF Pembrolizumab 200 mg Q3W Balar et al. ESMO 2016; abstract LBA32_PR. Primary Endpoints ORR in all patients ORR in patients with PD-L1 positive tumors Primary Endpoints: Planned interim analysis in first 100 patients Determine the PD-L1 high expression cutpoint ORR in all patients and PD-L1 positive population Secondary Endpoints: DOR, PFS, OS, and ORR in all patients, PD-L1 positive and PD-L1 high-expressing patients; safety and tolerability

11 KEYNOTE-052 (ASCO17 Update) N = 370 ORR: 29% CR: 7% O Donnell et al. ASCO 2017; Abstract 4502.

12 Approvals: Previously-treated Disease May 2016 Feb 2017 May 2017 Atezolizumab Nivolumab Durvalumab Avelumab Pembrolizumab Above agents are indicated in patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with (platinum-containing) chemotherapy.

13 IMvigor210 (Cohort 2) IMvigor210: Inoperable locally advanced or metastatic urothelial carcinoma Predominantly UC histology Tumor tissue evaluable for PD-L1 testing a Cohort 1 (N = 119): 1L cisplatin-ineligible Cohort 2 (N = 310): Platinum-treated muc Atezolizumab 1200 mg IV q3w until RECIST v1.1 progression Atezolizumab 1200 mg IV q3w until loss of clinical benefit Cohort 2-Specific Inclusion Criteria Progression during/following platinum (no restrictions on # prior lines of therapy) ECOG PS 0-1 CrCl 30 ml/min Key primary endpoint : Confirmed ORR: RECIST v1.1 (per central IRF) Key secondary endpoints : DOR, PFS, OS, safety Rosenberg et al. Lancet. 2016; 387:1909.

14 IMvigor210 (Cohort 2) All patients: ORR = 15% (5% CR) mos = 7.9 months Rosenberg et al. Lancet. 2016; 387:1909.

15 Phase Ia Trial of Atezolizumab in Pretreated Bladder Cancer N = 92 72% with 2 prior systemic therapies ORR 50% in PD-L1 high (IC2/3) ORR 17% in PD-L1 low (IC0/1) Petrylak et al. ASCO 2015; Abstract 4501.

16 OS by PD-L1 Status Petrylak et al. ASCO 2015; Abstract 4501.

17 Median Survival by Baseline Characteristics Petrylak et al. ASCO 2015; Abstract 4501.

18 Patterns of AE Occurrence Petrylak et al. ASCO 2015; Abstract 4501.

19 IMvigor211 Phase III Trial in Previously-treated Urothelial Cancer Patients with previously treated relapsed UBC (n = 767 [230 PD-L1+]) Primary endpoint: OS in IHC 2/3à 1/2/3à ITT Secondary endpoints: PFS, ORR, DOR FPI: Q FPI=first patient in; ITT=intent-to-treat. Vinflunine, paclitaxel, or docetaxel IV q3w until progression Atezolizumab 1200 mg IV q3w

20 IMvigor211 Study Design 20 Key Eligibility Criteria a muc with progression during or following platinum-based chemotherapy Primary endpoint: 2 prior lines of therapy OS Measurable disease 2-sided per RECIST = 0.05 v1.1 ECOG PS 0-1 Evaluable sample for OS: PD-L1 IC2/3 testing TCC histology as primary component (N = 931) Stratification OS: IC1/2/3 Factors No. of risk factors b (0 vs. 1/2/3) Liver metastases (yes vs. no) PD-L1 status (0/1 vs. 2/3) Chemotherapy (vinflunine vs. taxanes) OS: ITT Primary endpoint OS, tested hierarchically in pre-specified populations R 1:1 Atezolizumab Loss of 1200 mg q3w clinical benefit Key secondary endpoints: ORR, No crossover then PFS permitted per protocol ORR: IC2/3 Chemotherapy (investigator s choice) Vinflunine q3w ORR: Docetaxel IC1/2/3 q3w Paclitaxel q3w ORR: ITT Additional endpoints PFS: IC2/3 RECIST v1.1 progression Survival follow-up Efficacy: RECIST v1.1 ORR, PFS and DOR c Safety PROs: EORTC QLQ-C30 PFS: IC1/2/3 PFS: ITT 20 DOR, duration of response; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organisation for Research and Treatment of Cancer; PRO, patient-reported outcome; q3w, every three weeks; RECIST, Response Evaluation Criteria In Solid Tumors; TCC, transitional cell carcinoma. a ClinicalTrials.gov, NCT b Defined by time from prior chemotherapy < 3 mo, ECOG performance status > 0 and hemoglobin < 10 g/dl. c Confirmed response was not required for secondary efficacy endpoints. This analysis reports exploratory confirmed responses. Powles T, et al. EAS 2017, IMvigor211.

21 OS Analysis: IC2/3 Population Events/ Patients Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizumab 72/ mo (8.6, 15.5) 46% (37, 56) Chemotherapy 88/ mo (8.4, 12.2) 41% (32, 50) Overall Survival HR = 0.87 (95% CI: 0.63, 1.21) P = Months No. at Risk Atezolizumab Chemotherapy Powles T, et al. EAS 2017, IMvigor211. HR, hazard ratio.

22 OS Analysis: IC1/2/3 Population Events/ Patients Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizumab 220/ mo (8.2, 10.9) 40% (35, 46) Chemotherapy 232/ mo (7.4, 9.5) 33% (28, 39) Overall Survival HR = 0.87 (95% CI: 0.71, 1.05) P = Months No. at Risk Atezolizumab Chemotherapy Powles T, et al. EAS 2017, IMvigor211.

23 OS Analysis: ITT Population Events/ Patients Median OS (95% CI) 12-mo OS Rate (95% CI) Atezolizumab 324/ mo (7.8, 9.6) 39% (35, 44) Chemotherapy 350/ mo (7.2, 8.6) 32% (28, 37) Overall Survival HR = 0.85 (95% CI: 0.73, 0.99) P = Months No. at Risk Atezolizumab Chemotherapy Median follow-up duration in ITT population: 17.3 mo (range, 0 to 24.5 mo) 23 Powles T, et al. EAS 2017, IMvigor211.

24 OS by Chemotherapy Type Overall Survival 100 HR = 0.73 (95% CI: 0.58, 0.92) ITT With Taxane Months No. at Risk Atezolizumab Taxane OS was also examined in subgroups based on chemotherapy type at randomization Improved OS was observed with atezolizumab vs. taxanes Subgroup Median OS (95% CI) Atezolizumab 8.3 mo (6.6, 9.8) Taxane 7.5 mo (6.7, 8.6) 24 Powles T, et al. EAS 2017, IMvigor211.

25 Open-label, single-arm, phase II study Patients Metastatic or locally advanced muc Disease progression on a prior platinumbased therapy Evaluable PD-L1 tumor tissue sample a CheckMate 275: Study Design Treatment Nivolumab 3 mg/kg IV Q2W N = 270 Blinded independent review committee (BIRC) assessment of response using RECIST v1.1 Treat until progression b or unacceptable toxicity a Patients were required to have an evaluable tumor tissue sample for PD-L1 expression testing at screening, but were not excluded based on PD-L1 status. b Patients could have been treated beyond progression under protocol-defined circumstances. Adapted from Galsky et al. ESMO 2016.

26 CheckMate 275 ORR = 20% (2% CR) Sharma et al. Lancet Oncol. 2017;18:

27 Study 1108: Durvalumab Dose-escalation and Dose-expansion Study Powles et al. ASCO GU 2017; Abstract 286.

28 Study 1108 (Durvalumab) ASCO17 Update ORR CR All Patients (N = 191) 18% 4% 2 nd -line (N = 182) 18% 3% mos 18.2 mo - mpfs 1.5 mo - Hahn et al. ASCO 2017; Abstract 4525.

29 DANUBE Phase 3 Study Design Treatment-naïve patients Unresectable Stage IV (ie, T4b, any N; or any T, N2-N3; or M1) Transitional cell carcinoma a Randomization N = 1005 Durvalumab + tremelimumab N = 335 Durvalumab monotherapy N = 335 Standard of care N = 335 Objective disease progression Followup for OS a Transitional cell and mixed transitional/nontransitional cell histologies of the urothelium (including renal pelvis, ureters, urinary bladder, and urethra). Powles T, et al. J Clin Oncol. 2016;34:(suppl; abstr TPS4574).

30 Phase Ib JAVELIN Solid Tumor Trial of Avelumab: Trial Schema Open-label, multicenter phase Ib study in pts with confirmed solid tumors Advanced UC Cohort: Pts with histology or cytology confirmed metastatic UC after progression on or ineligible for platinum-based chemotherapy for metastatic disease; ECOG PS 0-1 (N = 241) Avelumab 10 mg/kg IV Q2W Treated until PD, unacceptable AE, or investigator decision Primary endpoint: ORR, safety Secondary endpoints: PFS, OS, and association of PD-L1 expression on tumor cells with clinical activity of avelumab Patel M, et al. ASCO GU Abstract 330.

31 Phase Ib JAVELIN Solid Tumor Trial of Avelumab (ASCO17 Update) ORR in patients with 6 months follow-up (N = 161): 17% (6% CR) N = 242 mos mpfs 7.4 mo 1.5 mo (6.6 wk) Apolo, et al. ASCO17; Abstract 4528.

32 KEYNOTE-045: Phase III Study Design CPS, combined positive score; PD, progressive disease. Bellmunt et al. SITC 2016; Abstract 02.

33 Median OS HR P Value Median PFS HR P Value Pembro Chemo 10.3 mo 7.4 mo Pembro Chemo 2.1 mo 3.3 mo Pembrolizumab Chemotherapy Data cutoff: Jan 18, 2017 Median follow-up: 18.5 mo ORR CR 21% 8% 11% 3% Bajorin et al. ASCO 2017, Abstract 4501.

34 Future Directions Combinations Adjuvant therapy Biomarkers

35 Addition of Ipilimumab to Nivolumab at Progression 10 patients who evidenced progression of disease on nivolumab. 1 PR, 4 SD after addition of ipilimumab. Modest increase in grade 3/4 toxicities. Callahan et al. ASCO GU 2017; Abstract 384.

36 Epacadostat (IDO1 Inhibitor) + Pembrolizumab in Advanced UC (Phase 1/2 ECHO-202/KEYNOTE-037) N = 40 Prior treatments for advanced disease: 0-1: 80% 2: 20% Grade 3/4 AEs N = 40 Rash 8% All Patients (N = 40) 0-1 Prior Lines (n = 32) 2 Prior Lines (n = 8) PD-L1 1% (n = 11) PD-L1 <1% (n = 8) Hyperglycemia 5% Fatigue 3% ORR 35% 38% 25% 64% 13% CR 8% 9% ALT increase 3% Lipase increase 3% Smith et al. ASCO 2017; Abstract 4503.

37 Rationale for VEGF Blockade in Bladder Cancer Antiangiogenic agents, particularly anti-vegfr-2 monoclonal antibodies (MAbs), may be capable of acting as chemosensitizing agents when given in combination with docetaxel, since this effect was demonstrated in mice when an anti-vegfr-2 MAb, DC101, was combined with paclitaxel. Anti-VEGFR-1 MAbs may inhibit metastasis, based on the observed impact of the anti-vegfr-1 MAb, MF1, on VEGFR-1-positive circulating hematopoietic progenitor cells in mice.

38 Binding of Ramucirumab to VEGFR-2 and Icrucumab to VEGFR-1 Inhibits Subsequent Signaling

39 Figure 2. Decreased Tumor Burden in Urothelial Carcinoma Patients (RECIST 1.1) 48% of evaluable patients experienced a decrease in target lesion ITT Population Objective response rate Cohort D N = 24 3 (13) a Disease control rate b 12 (50) Median duration of response, mo (95% CI) NR (4.6-NR) Median time to response, mo (95% CI) 2.8 ( ) Duration of stable disease Best overall response, n (%) 2.8 (1.9-NR) Complete response (CR) - Partial response (PR) 3 (13) Stable disease (SD) 9 (38) Progressive disease (PD) 11 (46) Not evaluable 1 (4) a All responders were PD-L1 positive. b Patients with best response of CR, PR, or SD. NR= not reached. Presented by Petrylak DP et al.

40 Ramucirumab + Docetaxel in Platinum- Pretreated, Advanced Bladder Cancer (RANGE) Patients with locally advanced or unresectable or metastatic urothelial carcinoma progressing on or after platinum-based therapy 1 prior chemotherapy for relapsed or metastatic disease N=531 Primary endpoint: PFS Secondary endpoints: OS, ORR, DOR Ramucirumab + Docetaxel Placebo + Docetaxel May 31, 2017: Primary endpoint of PFS met. ClinicalTrials.gov ID: NCT

41 Summary of Selected IO Combination Studies in Previously-treated Patients Sponsor/name Arms Line of therapy N Phase ClinicalTrials.gov Identifier BMS CA Nivolumab +/- ipilimumab 2 nd line 1150 I/II NCT NCI - Center for Cancer Nivolumab +/- ipilimumab in combination with 2 nd line 66 I/II NCT Research cabozantinib BMS CA Anti-LAG-3 With and Without nivolumab 2 nd line 360 I NCT CDX Combination of varlilumab (CDX1127) and 2 nd line 55 I NCT atezolizumab CPI CPI-444 +/- atezolizumab 2 nd line 534 I NCT Plexxikon Combining a CSF1R, KIT, FLT3 Inhibitor (PLX3397) 2 nd line 400 I/II NCT and pembrolizumab PsiOxus Therapeutics Enadenotucirev (oncolytic virus) +/- nivolumab 2 nd line 30 I NCT UC Davis Pembrolizumab (MK3475) + docetaxel or gemcitabine in platinum pre-treated urothelial cancer 2 nd line 38 I NCT Yale Ramucirumab, VEGFR2 inhibitor, + pembrolizumab 2 nd line 155 I NCT USC AstraZeneca Combination Therapy with pembrolizumab and sephb4-hsa Biomarker-driven treatment: combinations with durvalumab and inhibitors of FGFR, PARP, Wee1 2 nd line 60 II NCT nd line/ 3 rd line 110 I NCT

42 What are the studies evaluating checkpoint inhibition therapy as adjuvant treatment post cystectomy? What is the optimal patient population?

43 NCI Trial - Pembrolizumab Eligibility Histologically confirmed UC Radical cystectomy, ureterectomy, and/or nephrectomy performed 16 wk prior to registration High-risk disease No invasive cancer at the surgical margins No evidence of residual cancer or metastasis after surgery No adjuvant systemic therapy a Stratification Site of disease: upper tract vs. bladder cancer primary Neoadjuvant chemotherapy: yes vs. no Pathologic Stage: pt2/3n0 vs pt4n0/ptanyn1-3 PD-L1 status: positive vs. negative Endpoints Dual primary objectives To determine DFS and OS in patients with muscle-invasive bladder and upper-tract urothelial carcinoma treated with adjuvant pembrolizumab vs. observation. Secondary endpoints OS and DFS in PD-L1 positive subjects and PD-L1 negative subjects To characterize the safety and tolerability of pembrolizumab when administered in the adjuvant setting a Patients should be counseled appropriately and document refusal of cisplatin chemotherapy if eligible or be ineligible for cisplatin.

44 Phase III Randomized Adjuvant study of pembrolizumab in muscle invasive and locally advanced urothelial carcinoma (AMBASSADOR ) versus Observation Eligibility MIBC or UTUC h/o cystectomy or nephrectomy within 16 weeks pt2-4anx or ptxn+ post neoadjuvant chemotherapy OR pt3-4nx or pn+ post surgery with no chemotherapy Stratify PDL1 +/- Bladder vs upper-tract Neoadjuvant chemotherapy yes/no Pathologic stage: pt2/3/4an0 vs pt4bnx orn1-3 R A N D O M I Z E 1:1 N = 739 Pembrolizumab 200mg q3w 1 year Observation q3w O V E R A L L S U R V I V A L D I S E A S E F R E E S U R V I V A L Co-primary

45 Other Adjuvant Trials Agent (Trial) Phase N Setting Treatment Arms Primary Endpoint(s) ClinicalTrials.g ov ID Atezolizumab (IMvigor010) III 700 Post-resection, high risk a Atezolizumab vs observation DFS NCT Nivolumab (CheckMate 274) III 640 Post-resection, high risk a Nivolumab vs placebo DFS NCT Durvalumab (DUART) I/II 42 Locally advanced, unresectable b Durvalumab + RT Safety, PFS, DCR NCT a Patients who have not received prior neoadjuvant platinum-based chemotherapy may enroll if cisplatin ineligible. b Cisplatin-ineligible patients may enroll.

46 Biomarkers In bladder cancer, PD-L1 staining appears to be associated with higher response rate, and may be linked to overall survival; 1 however, multiple assays exist and are under evaluation in bladder cancer. Other biomarkers beyond PD-L1 are needed. Data in multiple cancer types suggests that mutation load is associated with treatment outcome with immune checkpoint blockade. 2,3 Gene expression 1. Petrylak et al. subtypes ASCO 2015; Abstract may 4501; be predictive 2. Snyder et al. N of Engl ORR J Med. with 2014;371: ; immunotherapy. 4,5 3. Rizvi et al. Science. 2015;348: ; 4. Rosenberg et al. ASCO 2016; Abstract 104; 5. Choi et al. Nat Rev Urol. 2014;11:

47 Examples of Different Staining Patterns and Antibodies SP-142 5% 1 but < 5% < 1% IC2/3 SP263 IC1 IC0 Rosenberg et al. ESMO 2016 Abstract 22C3 Massard C, et al. J Clin Oncol. 2016;34(26): c/o E. Plimack

48 Other Biomarkers Beyond PD-L1 IHC are Needed Bladder cancer has high mutation burden, second only to lung cancer and melanoma 1 Data in multiple cancer types suggests that mutation load is associated with treatment outcome with immune checkpoint blockade 2,3 1. Alexandrov LB, et al. Nature. 2013;500(7463): Snyder A, et al. N Engl J Med. 2014;371(23): Rizvi NA, et al. Science. 2015;348(6230):

49 Estimated Mutation Load Associated with Higher Objective Responses with Atezolizumab in Platinum-pre-treated Patients Estimated using a targeted panel Focuses on non-hotspot alterations Extrapolates from 3% of genome covered in assay RECIST v1.1 response Responder Non-responder Mutation Load/MB All (n = 150) I II Luminal III Basal IV Mutation Load/MB IC0/1 IC2/3 Rosenberg JE, et al. Lancet. 2016;387(10031):

50 Biomarkers Beyond PD-L1: Mutation Load is Associated with OS in Patients Treated with Atezolizumab OS Probability 100% 75% 50% 25% 0% Cohort 2 Platinum-treated muc Q4 Median load quartile (range) Q4: ( > 16.0 to 62.2) Q3: ( > 8.1 to 16.0) Q2: ( > 5.4 to 8.1) Q1: ( 0.9 to 5.4) P = a Days OS Probability 100% 75% 50% 25% 0% Cohort 1 1L cisplatin-ineligible muc Median load quartile (range) Q4: ( > 13.5 to 46.8) Q3: ( > 9.0 to 13.5) Q2: ( > 5.4 to 9.0) Q1: ( 0 to 5.4) P = a Q Days Mutation load associated with ORR Quartile-split mutation load was associated with OS in platinum-treated patients (cohort 2) Similar results were seen for 1L cisplatin-ineligible patients (cohort 1) In both cohorts, patients with the highest median mutation load (Q4) had significantly longer OS versus those in Q1-Q3a Rosenberg JE, et al. Presented at: ASCO 2016; June 3-7, 2016; Chicago, IL. Abstract 104.

51 Biomarkers Beyond PD-L1: Expression Subtype Associated with ORR ORR, % n = 73 n = 52 n = 38 n = 36 Gene expression data used to classify IMvigor210 tumor samples recapitulated TCGA subtypes 1,2 Responses occurred in all subtypes, but ORR was significantly higher in luminal II versus other subtypes (P=.0072) What might be the drivers of this subtype-specific response? 0 TCGA, The Cancer Genome Atlas. Data cutoff: March 14, Cancer Genome Atlas Research Network. Nature. 2014;507(7492): Rosenberg JE, et al. Lancet. 2016;387(10031): I II III IV Luminal Basal RECIST v1.1 response PD SD PR CR Urothelium 1. Rosenberg JE, et al. J Clin Oncol. 2016;34(suppl):Abstract Choi W, et al. Nat Rev Urol. 2014;11(7): Luminal Basal

52 Biomarkers Beyond PD-L1 Rosenberg JE, et al. Presented at: ASCO 2016; June 3-7, 2016; Chicago, IL. Abstract 104. Luminal I: Immune desert Luminal II: Inflamed Basal: Immune suppressed Urothelium Luminal Basal Increased responses Luminal I tumors have low T eff expression Luminal II tumors have high T eff and low stromal gene expression Basal tumors have high T eff and high stromal gene expression

53 Association Between UC Molecular Subtype, 25-gene Interferon-γ Signature, and Response to Nivolumab Basal 1 and luminal 2 have higher response rates versus the other 2 subtypes Interferon-γ genes are enriched in responders/sd versus those with progressive disease (P<.01) Complete Response a Partial Response Stable Disease Progressive Disease P< % 2 75% 50% 25% 0% Cluster Luminal 1 (Luminal 1 Cluster Luminal 2 (Luminal 2 (Cluster 1) n=661) (Cluster 2) n=552) n=66 n= Cluster Basal 3 (Basal 1 1) (Cluster n=23 3) n=23 Molecular Subtype Basal 2 CR, 0%; luminal 1 CR,1.5%; luminal 2 CR, 1.8% c/o Galsky, ESMO Cluster Basal 4 (Basal 2 2) (Cluster n=33 4) n=33 Signature score CR/PR/SD PD Response Signature score, 25-gene interferon-γ signature expression

54 Presented by: Daniel P. Petrylak Enfortumab Vedotin: Proposed Mechanism of Action Enfortumab Vedotin is being co-developed by Seattle Genetics, Inc. and Astellas Pharma Inc.

55 Presented by: Daniel P. Petrylak Screening of Nectin-4 Expression in muc At screening, patients with muc had samples that were centrally assessed by immunohistochemistry (IHC) for Nectin-4 Almost all patient (97%) samples showed Nectin-4 expression Expression of Nectin-4 was high (median H-score 280 out of a 300 maximum score) Due to the above findings, prescreening for Nectin-4 is no longer an eligibility requirement for subjects with muc H- score Pa+ents Gray bars indicate patients with Nectin-4 H-score <150 Blue bars indicate patients with H-scores of 150 Note: data cutoff November 2016, N=186

56 Maximum Reduction from Baseline in Total Tumor Burden in Patients with muc on Enfortumab Vedotin Presented by: Daniel P. Petrylak

57 Presented by: Daniel P. Petrylak Investigator-Assessed Response in Patients with muc on Enfortumab Vedotin 0.5 mg/kg (n=2) 0.75 mg/kg (n=12) 1.0 mg/kg (n=27) 1.25 mg/kg (n=30) Total (N=71) a CR, n (%) (7) 1 (3) 3 (4) PR, n (%) 1 (50) 4 (33) 6 (22) 15 (50) 26 (37) SD, n (%) 1 (50) 6 (50) 9 (33) 6 (20) 22 (31) PD, n (%) 0 2 (17) 6 (22) 6 (20) 14 (20) NE, n (%) (15) 2 (7) 6 (9) ORR b (95% CI) 50 (unconfirmed) (1.3, 98.7) 33 (9.9, 65.1) 30 (13.8, 50.2) 53 (34.3, 71.7) 41 (29.3, 53.2) DCR b (95% CI) 100 (15.8, 100) 83 (51.6, 97.9) 63 (42.4, 80.6) 73 (54.1, 87.7) 72 (59.9, 81.9) Orange box indicates recommended phase 2 dose. CR, complete response; SD, stable disease; PR, partial response; DCR, disease control rate (DCR=CR+PR+SD); ORR (unconfirmed), overall response rate (ORR=CR+PR). a Patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. b 95% CI based on the Clopper-Pearson method.

58 Presented by: Daniel P. Petrylak Response in muc Patients with Prior CPI, Taxane Treatment, or Liver Metastases on Enfortumab Vedotin Prior CPI Treatment a Prior Taxane Treatment Liver Metastases 1.25 mg/kg (n=17) All Doses b (N=32) 1.25 mg/kg (n=10) All Doses b (N=29) 1.25 mg/kg (n=5) All Doses b (N=19) CR, n (%) 0 1 (3) 1 (10) 1 (3) 0 1 (5) PR, n (%) 8 (47) 13 (41) 5 (50) 11 (38) 3 (60) 8 (42) SD, n (%) 5 (29) 9 (28) 0 (0) 8 (28) 1(20) 4 (21) ORR c (95% CI) (unconfirmed) 47 (23.0, 72.2) 44 (26.4, 62.3) 60 (26.2, 87.8) 41 (23.5, 61.1) 60 (14.7, 94.7) 47 (24.4, 71.1) DCR c (95% CI) 77 (50.1, 93.2) 72 (53.3, 86.3) 60 (26.2, 87.8) 69 (49.2, 84.7) 80 (28.4, 99.5) 68 (43.4, 87.4) Data cut-off date April 28, Data presented as n (%), unless otherwise indicated. CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); NE, not evaluable; PD, progressive disease; PR, partial response; ORR (unconfirmed), overall response rate (ORR=CR+PR); SD, stable disease. a No patients with prior CPI treatment received 0.5 mg/kg enfortumab vedotin. b Evaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. c Data presented as % (95% confidence interval [CI]); 95% CI based on the Clopper-Pearson method.

59 Presented by: Daniel P. Petrylak Response in muc Patients with Prior CPI, Taxane Treatment, or Liver Metastases on Enfortumab Vedotin Prior CPI Treatment a Prior Taxane Treatment Liver Metastases 1.25 mg/kg (n=17) All Doses b (N=32) 1.25 mg/kg (n=10) All Doses b (N=29) 1.25 mg/kg (n=5) All Doses b (N=19) CR, n (%) 0 1 (3) 1 (10) 1 (3) 0 1 (5) PR, n (%) 8 (47) 13 (41) 5 (50) 11 (38) 3 (60) 8 (42) SD, n (%) 5 (29) 9 (28) 0 (0) 8 (28) 1(20) 4 (21) ORR c (95% CI) (unconfirmed) 47 (23.0, 72.2) 44 (26.4, 62.3) 60 (26.2, 87.8) 41 (23.5, 61.1) 60 (14.7, 94.7) 47 (24.4, 71.1) DCR c (95% CI) 77 (50.1, 93.2) 72 (53.3, 86.3) 60 (26.2, 87.8) 69 (49.2, 84.7) 80 (28.4, 99.5) 68 (43.4, 87.4) Data cut-off date April 28, Data presented as n (%), unless otherwise indicated. CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); NE, not evaluable; PD, progressive disease; PR, partial response; ORR (unconfirmed), overall response rate (ORR=CR+PR); SD, stable disease. a No patients with prior CPI treatment received 0.5 mg/kg enfortumab vedotin. b Evaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. c Data presented as % (95% confidence interval [CI]); 95% CI based on the Clopper-Pearson method.

60 Presented by: Daniel P. Petrylak Response in muc Patients with Prior CPI, Taxane Treatment, or Liver Metastases on Enfortumab Vedotin Prior CPI Treatment a Prior Taxane Treatment Liver Metastases 1.25 mg/kg (n=17) All Doses b (N=32) 1.25 mg/kg (n=10) All Doses b (N=29) 1.25 mg/kg (n=5) All Doses b (N=19) CR, n (%) 0 1 (3) 1 (10) 1 (3) 0 1 (5) PR, n (%) 8 (47) 13 (41) 5 (50) 11 (38) 3 (60) 8 (42) SD, n (%) 5 (29) 9 (28) 0 (0) 8 (28) 1(20) 4 (21) ORR c (95% CI) (unconfirmed) 47 (23.0, 72.2) 44 (26.4, 62.3) 60 (26.2, 87.8) 41 (23.5, 61.1) 60 (14.7, 94.7) 47 (24.4, 71.1) DCR c (95% CI) 77 (50.1, 93.2) 72 (53.3, 86.3) 60 (26.2, 87.8) 69 (49.2, 84.7) 80 (28.4, 99.5) 68 (43.4, 87.4) Data cut-off date April 28, Data presented as n (%), unless otherwise indicated. CR, complete response; CPI, checkpoint inhibitor, DCR, disease control rate (DCR=CR+PR+SD); NE, not evaluable; PD, progressive disease; PR, partial response; ORR (unconfirmed), overall response rate (ORR=CR+PR); SD, stable disease. a No patients with prior CPI treatment received 0.5 mg/kg enfortumab vedotin. b Evaluable patients must have at least one post-baseline assessment; responses assessed per RECIST 1.1. c Data presented as % (95% confidence interval [CI]); 95% CI based on the Clopper-Pearson method.

61 Conclusions Checkpoint inhibition therapy demonstrates significant antitumor activity in advanced urothelial carcinoma: As initial therapy in cisplatin-ineligible patients. In patients with cisplatin-pretreated disease. Trials are ongoing to explore immunotherapy-based combinations and the use of immunotherapy in earlier stages of disease. A thorough understanding of the markers of resistance and response will help to designing future trials in earlier disease.